TECHNICAL FIELD
[0001] The present disclosure relates to methods of norketotifen-treatment of medical conditions
that are mediated through histamine H-4 receptors in mammals.
BACKGROUND
[0002] Four histamine receptors (H-1, H-2, H-3, H-4) have been identified, all of which
are G protein-coupled receptors. The four different receptors are expressed on various
cell types and exert their effects through different intracellular signaling mechanisms,
which may in part be related to the diverse effects of histamine in different cells,
tissues and organs.
[0003] The human histamine H-4 receptor is active constitutively, as is also the case with
human histamine H-1, H-2 and H-3 receptors. Thus, like all other histamine receptor
inhibitors, histamine H-4 receptor inhibitors are inverse agonists on the human histamine
receptors.
[0004] Several potent and selective histamine H-4 receptor ligands have been described,
such as for example JNJ 7777120, JNJ 10191584 and 4-methylhistamine. Such ligands
will bind to all human histamine H-4 receptors, wherever those receptors are expressed
in the body, such as for example, in bone marrow and white blood cells. The disadvantage
of these compounds is that they act with high potency inhibiting histamine H-4 receptors
throughout the body, increasing the likelihood of unwanted systemic side effects.
[0005] What is needed are improved methods of selectively treating medical conditions associated
with histamine H-4 receptors at the biophases of those conditions. Note that
WO01/19367A1 discloses optically active isomers of ketotifen and therapeutically active metabolites
thereof and that
WO2008/153761A1 discloses methods of treating severe allergic reaction through the use of a mast
cell stabilizer (e.g. ketotifen).
SUMMARY
[0006] The claimed invention provides RS-norketotifen or a pharmaceutically acceptable salt
thereof for use in a method of treating histamine H-4 receptor-related pruritus in
a mammal in need of such treatment, said method comprising orally administering to
the mammal in need thereof a therapeutically effective amount of said RS-norketotifen
or a pharmaceutically acceptable salt thereof, wherein the histamine H-4 receptor-
related pruritus is a) associated with a dermal disorder selected from autoimmune
dermatitis, contact dermatitis, dermal scleroderma, folliculitis, an insect bite,
melanoma, a parasite, scabies, sunburn, a wart, xerosis, a mole, and idiopathic pruritus
or b) associated with a nerve disorder selected from multiple sclerosis, a neuropathy,
a scar, and shingles. Preferred embodiments are set out in the appended, dependent
claims. Administration of the therapeutically effective amount of RS-norketotifen
or a pharmaceutically acceptable salt thereof is expected to avoid systemic histamine-H-4-related
adverse drug effects, because the orally administered amount of the drug accumulates
in the skin, which is the largest organ in the body.
[0007] In addition, we describe a method of treating a mammal in need of treatment for histamine
H-4 receptor-related pruritus without inducing systemic side effects that comprises
orally administering to the mammal in need thereof a therapeutically effective amount
of a biophase-selective histamine H-4 receptor inhibitor, wherein the biophase-selective
histamine H-4 receptor inhibitor is norketotifen, an isomer of norketotifen, or a
pharmaceutically acceptable salt of racemic or isomeric norketotifen. Pruritus (itch)
is a sensation that causes the desire or reflex to scratch. Pain and pruritus have
anatomical and physiological similarities, but while pain evokes a withdrawal reflex,
pruritus creates a scratching reflex. Often multiple scratches are evoked, usually
called "bouts of scratches". The word "pruritus" is Latin for "itch".
BRIEF DESCRIPTION OF THE FIGURES
[0008] Figure 1 shows the effects of test articles on histamine-induced pruritus in mice.
(N = 8, if not differently stated)
DETAILED DESCRIPTION
[0009] Histamine H-4 receptors are known to be expressed in the skin as well as in the pulmonary
and gastrointestinal tissues of humans and of animals. Histamine H-4 receptors are
also expressed in bone marrow, and serious side effects, such as for example, agranulocytosis,
are believed to be related to the activity of potent histamine H-4 receptor inhibitors.
Without being held to theory, it is believed that systemic adverse effects will be
less pronounced for compounds that are selectively distributed to specific biophase
organs or tissues where the compounds may accumulate in concentrations that are higher
than the systemic plasma concentration. Such compounds will reach concentrations that
inhibit histamine H-4 receptors locally in the specific organs or tissues, thereby
reducing the systemic exposure and the incidence of systemic side effects. Thus, rather
than increasing the potency or the dose of histamine H-4 receptor ligands, it may
be advantageous to use a histamine H-4 receptor inhibitor that accumulates at the
biophase(s) for diseases. Such compounds will selectively express histamine H-4 receptor
inverse agonistic activity where they are accumulated, while avoiding the adverse
effects of evenly distributed ligands with high affinity for the histamine H-4 receptors.
[0010] As used herein, the term biophase refers to the site(s) where a drug expresses its
therapeutic activity. For example, if a receptor is associated with a disorder in
the skin, then the biophase is the skin.
[0011] As used herein, a potent histamine H-4 receptor inverse agonist has a Ki less than
3.0E-7M, while moderately active compounds have Ki between 3.0E-6M and 3.0E-7M.
[0012] It is highly advantageous if compounds with moderate histamine H-4 receptor activity
accumulate where they are anatomically therapeutically active; the moderate activity
will not express systemic adverse effects, such as for example agranulocytosis. Such
compounds are herein called biophase-selective histamine H-4 receptor ligands or biophase-selective
histamine H-4 inhibitors or biophase-selective histamine H-4 inverse agonists.
[0013] It has specifically been found that after oral administration, racemic norketotifen
(RS-norketotifen) and the isomers thereof (R-norketotifen, S-norketotifen) accumulate
in the skin. The skin is the biophase for dermal diseases and the pharmacokinetic
exposure parameters - area under the curve, half-lives and mean residence times -
of norketotifen in this biophase have been found to significantly exceed the corresponding
parameters in the systemic circulation (See, e.g., Example 4.) The high concentrations
of these compounds in skin (See, e.g., Example 4) will inhibit the histaminic H-4
receptors (See, e.g., Examples 2 and 3), particularly since these compounds potently
decrease the concentrations of available histamine at the biophase (See, e.g., Example
1). Thus, RS-, Rand S- norketotifen, as well as other histamine H-4 receptor inhibitors
that are distributed in high concentrations in the skin, can advantageously be used
to treat diseases or medical conditions associated with dermal histamine H-4 receptors.
[0014] Further, norketotifen and the isomers thereof have moderate affinity for histamine
H-4 receptors. This moderate affinity combined with the localization in the biophases
of the skin and lungs avoids adverse effects induced by systemically active histamine
H-4 receptor inhibitors.
[0015] Disclosed herein is a method of treating a mammal in need of treatment for histamine
H-4 receptor-related pruritus, comprising orally administering to the mammal in need
thereof a therapeutically effective amount of a biophase-specific H-4-receptor inhibitor.
Optionally, the biophase-selective histamine H-4 receptor inhibitors are RS-, R- or
S-norketotifen, or pharmaceutically acceptable salts thereof, specifically RS-norketotifen
or pharmaceutically acceptable salts thereof. Optionally, the histamine H4-receptor-related
disorder is not histamine H-1-related.
[0016] Exemplary histamine H-4 receptor-related dermal disorders include histamine H-4 receptor-related
pruritic disorders. Activation of dermal histamine H-4 receptors by histamine or other
endogenous H-4 receptor agonists, such as for example CCL16, results in pruritus that
is caused by pruritic mechanisms that are regulated by histamine H-4 receptors.
[0017] Also described is a method of treating a mammal in need of treatment for histamine
H-4 receptor-related pruritus that comprises orally administering to the mammal in
need thereof a therapeutically effective amount of a biophase-selective histamine
H-4 receptor inhibitor, wherein the biophase-selective histamine H-4 receptor inhibitor
is norketotifen, an isomer of norketotifen, or a pharmaceutically acceptable salt
thereof. Optionally, the histamine H-4 receptor-related pruritus is resistant to treatment
with histamine H-1 receptor inhibitors.
[0018] Pruritus (itching) is an unpleasant sensation that - contrary to pain - elicits the
desire to scratch. Histamine H-4 receptor-related pruritus can be associated with
various disorders and conditions, such as for example:
Adverse Effects of Prescription Drugs: antibiotics, antifungals, pain relievers;
Dermal Disorders: autoimmune dermatitis, contact dermatitis, dermal scleroderma, folliculitis, idiopathic
dermatitis, infections, insect bites, melanoma, parasites, scabies, sunburn, warts,
xerosis and dermal conditions such as moles, hyperpigmentation, hypopigmentation and
rashes;
Systemic Disorders: anemia, cholestasis, diabetes, Hodgkin lymphoma, iron deficiency, chronic renal failure,
systemic scleroderma, multiple sclerosis, uremia, and conditions such as pregnancy;
Nerve disorders: multiple sclerosis, neuropathic pruritus, scars, shingles;
Psychological disorders: anxiety, depression, emotional stress, neurodermatitis, psychological trauma, psychoses;
and
Idiopathic pruritus: various forms of pruritus, where the cause for the itching has not been successfully
determined.
[0019] Scratching behavior is a sign of pruritus and can be studied in humans and in mice
after intradermal injections of histamine. Pruritus following histamine injections
is not inhibited by histamine H-1 inhibitors, such as desloratadine (Clarinex® Merck
Sharp & Dohme), diphenhydramine (Benadryl® McNeil) or fexofenadine (Allegra® Sanofi
Aventis). Histamine-induced pruritus is potently inhibited by histamine H-4 inhibitors,
such as for example JNJ7777120 and norketotifen (Example 5).
[0020] The methods for treatment of pruritus, disclosed herein, are useful in the treatment
of non-humans as well as humans. While it is well known that the human histamine H-4
receptor expresses constitutive activity, it is possible that non-human histamine
H-4-receptors do not express constitutive activity. If it is confirmed that the canine
and feline histamine H-4 receptor does not express constitutive activity and/or norketotifen
therefore proves not to be an inverse histamine H-4 receptor agonist on the canine
histamine H-4 receptor, the correct terminology herein shall be "antagonist" or "inhibitor"
rather than "inverse agonist". Therefore, and to improve clarity with regard to histamine
H-4 receptors, the terms antagonist, inhibitor and inverse agonist will herein be
considered as homologs and will be alternatingly used. The human histamine H-4 receptor
has a high homology with the canine histamine H-4 receptor, the homology being 71
percent.
[0021] Another advantage of the use of norketotifen and its isomers is that those compounds
express inhibitory activities at both histamine H-1 receptors and histamine H-4 receptors.
There is a benefit to inhibiting the activities of both H-1 and H-4 receptors, since
co-administration of histamine H-1 and histamine H-4 receptor inhibitors can completely
inhibit some pruritic effects, such as for example types of pruritus with high intradermal
concentrations of histamine. It is believed that the histamine H-4-receptor mediated
pruritic activity is initiated locally in the skin, where pruritogenic mediators activate
receptors on neuronal C-fibers. However, the mechanisms for the potentiated antipruritic
activities of histamine H-1 receptor inhibitors and histamine H-4 receptor inhibitors
are presently not understood.
[0022] Despite the advantages of combinations of compounds that inhibit histamine H-1 receptors
with compounds that inhibit H-4 receptors, no compound with a combination of histamine
H-1 receptor and histamine H-4 receptor inhibitory activities has, to our knowledge,
been described previously. Norketotifen and the isomers thereof have such combined
activities.
[0023] Not all types of pruritus are inhibited by histamine H-4 receptor inhibition. Thus,
for example, the selective histamine-4 receptor inhibitor JNJ7777120 failed to inhibit
pruritus induced by interleukin-31 (IL-31) in a recent study.
[0026] Norketotifen is the active metabolite of ketotifen, which is a Generation-1 antihistamine.
Ketotifen may be the most potent antihistamine ever marketed, but it is also the most
sedating of all marketed antihistamines. The sedative effects of ketotifen are strictly
dose-limiting and doses higher than 1 mg, bid are rarely used. It is currently believed
that approximately 0.5 mg norketotifen is formed in the human body for every 1 mg
of ketotifen that is administered. The metabolism -- a demethylation of the piperidine
nitrogen -- takes place in the liver. The sedation by ketotifen is caused by ketotifen
per se (the "prodrug") while the disease-modifying effects of the drug are believed
to be due to the metabolite norketotifen. The currently used therapeutic doses of
ketotifen - 1 mg bid to humans - are not high enough to offer therapeutic activity
by inhibition of histamine H-4 receptor activity. (See, e.g., Example 3, Table 3).
[0027] Repeat-dose pharmacological and toxicological studies have now been performed in
dogs and it has surprisingly been found that daily doses up to 20 mg/kg/day of racemic
or isomeric norketotifen can be given chronically to dogs without causing sedation
or other adverse events. Doses up to 28 mg/kg/day did not cause sedation and were
tolerated by the dogs, but single oral doses of norketotifen of 4 mg/kg to 20 mg/kg
are preferred to obtain inhibition of H-4 receptors in the lungs and in the skin of
dogs. Dogs vomit spontaneously for a variety of benign reasons - to expel unwanted
content from their stomach, as a result of gastric irritation or in response to colonic
irritation. In recent toxicological studies in dogs of various drugs, including isomeric
norketotifen, vomiting occurred in both control groups and drug groups and may have
been treatment-related, rather than drug-related. The unexpectedly low systemic toxicity
of norketotifen and the isomers thereof is believed to be due to low systemic (plasma)
concentrations, caused by the fact that norketotifen and the isomers thereof are not
circulating in plasma but are accumulating in the skin, which is the largest organ
in the body.
[0028] Similarly, it has been found that doses of 5 mg and 10 mg of norketotifen in humans
also do not produce sedation when tested in human subjects.
[0029] It is presently estimated that inhibition of histamine H-4 receptor activity at the
biophases in mammals suffering from histamine H-4 receptor-related dermal or pulmonary
disorders, will occur at oral doses of norketotifen or an isomer thereof from approximately
2 mg/day to approximately 500 mg/day, which leaves a wide safety margin. Useful doses
of racemic or isomeric norketotifen to human patients suffering from said disorders
are between 2 mg/day and 500 mg/day. More preferred is a daily oral dose of 2 mg/day
to 40 mg/day to a human patient and most preferred is a human dose of 2 mg/day to
20 mg/day of norketotifen or an isomers thereof to human patients suffering from histamine
H-4 receptor-related dermal or pulmonary diseases.
[0030] Useful oral doses of racemic norketotifen or an isomer thereof are 2 mg/kg/day to
28 mg/kg/day to dogs suffering from pruritus diseases. More preferred are oral doses
ranging from 4 mg/kg/day to 20 mg/kg/day of racemic norketotifen, or an isomer thereof,
to dogs suffering from pruritic diseases.
[0031] Also described are pharmaceutical compositions, which comprise the compound norketotifen,
its isomers, and salts, formulated together with one or more pharmaceutically acceptable
carriers.
[0032] Pharmaceutical compositions for oral administration of solid dosage forms include
capsules, granules, pills, powders and tablets. In solid dosage forms, the active
compound may be mixed with one or more pharmaceutically acceptable excipients or carriers
(such as for example sodium citrate, dicalcium phosphate), fillers or extenders (such
as for example starch, lactose, sucrose, glucose, mannitol, silicic acid), binders
(such as for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,
sucrose, acacia), humectants (such as for example glycerol), solution retarding agents
(such as for example paraffin), disintegrating agents (such as for example agar-agar,
calcium carbonate, starch, alginic acid, silicates, sodium carbonate), absorption
accelerators (such as for example quaternary ammonium compounds), wetting agents (such
as for example cetyl alcohol, glycerol monostearate), absorbents (such as for example
kaolin, bentonite clay), lubricating agents (such as for example talc, calcium stearate,
magnesium stearate, polyethylene glycols, sodium lauryl sulfate), and/or other excipients,
such as for example buffering agents.
[0033] Solid forms of capsules, granules, pills, and tablets can have coatings and/or shells
(such as for example enteric coatings) known in the art. The compositions may also
be designed to release the active ingredient(s) in a certain part of the gastrointestinal
tract or in a controlled release, slow-release or in a delayed-release manner. The
active compound(s) can also be microencapsulated with one or more of the above-mentioned
excipients or other suitable excipients.
[0034] Liquid dosage forms for oral administration may be preferred administration forms
to children suffering from pruritus. Such formulations include for example pharmaceutically
acceptable solutions, emulsions, solutions, suspensions, syrups and elixirs. The liquid
dosage form may also contain excipients known to those skilled in the art of drug
formulations, such as for example diluents (such as for example water, other solvents
and solubilizing agents, and mixtures thereof), and emulsifiers (such as for example
ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, butylene glycol, dimethyl formamide, oils, oleic acid,
glycerol, polyethylene glycols, sorbitan fatty esters, and mixtures thereof. The oral
compositions may also include other excipients as known to those skilled in the art.
[0035] The compositions described here can also include other drugs with antipruritic activity,
as for example a corticosteroid. Due to the antipruritic activity of norketotifen
or the isomers thereof, a beneficial steroid-sparing effect will be possible when
treating patients suffering from various types of pruritic disorders.
[0036] The invention is further illustrated by the following non-limiting examples, noting
that the claimed invention is limited to RS-norketotifen or a pharmaceutically acceptable
salt thereof for use in a method as set out in claim 1 of the appended claims. Example
1. Inhibition of histamine release from pro-inflammatory cells
[0037] Histamine is excessively released from granulocytes in patients with pruritic diseases.
The inhibition of histamine release from human granulocytes (leukocytes; buffy coat)
by test articles was studied. Leukocytes were obtained from blood from healthy human
volunteers and release of histamine was induced by incubation (20 min/37°C) of the
buffy coats with the calcium ionophore A23187 (5 µM) in the presence or absence of
a test article. Histamine was analyzed by enzyme-immune assays, using commercially
available kits and a microplate reader (MRX, Dynatech). The test articles were evaluated,
in duplicate, at five concentrations.
Table 1. Inhibition of histamine release from human granulocytes
Test article |
Inhibition of mediator release IC50 (µM) |
Ketotifen |
91 |
Norketotifen |
9.2 |
[0038] Norketotifen was approximately 10 times more potent than ketotifen as an inhibitor
of histamine release from human inflammatory cells. Thus, norketotifen will potently
decrease the concentration of histamine in inflamed tissues.
Example 2. Binding to Histamine H-1 Receptors
[0039] Affinities of the test compounds for peripheral human histamine H-1-receptors were
assessed using receptor-binding assays. The specific binding of the radioactive ligand
to the receptor was defined as the difference between total binding and nonspecific
binding, determined in the presence of excess unlabeled ligand. Ki-values were determined
according to the Cheng-Prusoff equation.
Table 2. Inhibition of human histamine H-1 Receptor (IC50)
|
Human H-1 receptors IC50 (µM) |
RS-NORKETOTIFEN (NORK) |
11 |
S-NORKETOTIFEN (SNORK) |
23 |
R-NORKETOTIFEN (RNORK) |
17 |
KETOTIFEN |
2.3 |
LORATADINE (Claritin®*) |
1,500 |
DESLORATADINE (Clarinex®) |
16 |
DIPHENHYDRAMINE (Benadryl®) |
84 |
* Loratadine is the low-activity prodrug for desloratadine. |
[0040] Norketotifen and the isomers thereof had high affinity for histamine H-1-receptors,
similar to desloratadine and better than diphenhydramine.
[0041] The effects of the reference compounds (ketotifen, loratadine, desloratadine and
diphenhydramine) verify the previously known receptor binding activities of these
compounds, thereby validating the test methodology.
Example 3. Binding to Histamine H-4 Receptors
[0042] Affinities of the test compounds for peripheral human histamine H-4-receptors were
assessed using receptor-binding assays. The specific binding of the radioactive ligand
to the receptor was defined as the difference between total binding and nonspecific
binding, determined in the presence of excess unlabeled ligand. [
3H]-histamine was used as the ligand in this study and the affinity values were determined
according to the Cheng-Prusoff equation.
Table 3. Affinity for human histamine H-4 Receptor
|
Human H-4 receptor affinity (Ki) |
RS-NORKETOTIFEN (NORK) |
2.0E-0.6M |
S-NORKETOTIFEN (SNORK) |
1.1E-06M |
R-NORKETOTIFEN (RNORK) |
2.3E-06M |
KETOTIFEN |
2.1E-05M |
DESLORATADINE (Clarinex®) |
1.6E-05M |
DIPHENHYDRAMINE (Benadryl®) |
1.1E-05M |
[0043] RS-, S- and R-norketotifen had affinity for the H-4 receptor, albeit lower affinity
than the published corresponding values for super-potent and systemically active selective
H-4 -receptor active compounds, such as for example JNJ 7777120. It is not believed
that RS-, S- and R-norketotifen will express systemic reversal of the activity of
H-4 receptors unless the compounds appear in high concentrations at the receptor sites.
[0044] As known to those skilled in the art of pharmacology, high agonist concentrations
are needed in these studies since the Cheng-Prusoff equation is resulting in erroneous
values at low concentrations of agonists.
[0045] It is believed to be of therapeutic importance that norketotifen inhibits both histamine
H-4 and histamine H-1 receptors since a potentiation of the antipruritic activity
of histamine H-4 inhibition by histamine H-1 inhibition has been reported in the art,
although histamine H-1 inhibition by itself has no antipruritic effects, as described
in the art and as shown by the present results (Example 5; Figure 1).
Example 4: Dermal Drug Accumulation after Oral Administration
[0046] Five male beagle dogs, weighing 11.2 - 13.9 kg (2 - 4 years old) were used in the
study. All animals were administered gelatin capsules containing oral doses of the
test article 8.0 mg/kg/day as a hydrogen fumarate salt, equal to 5.6 mg/kg/day of
the free base. The animals were dosed once daily for four consecutive weeks followed
by daily observations for an additional two-week washout period.
[0047] Multiple plasma samples and skin biopsies were taken from each dog on Day 1 and Day
28 of drug administration. The plasma and skin samplings were performed at pre-dose,
and at 2, 6, 12 and 24 hours post-dose. Plasma and skin samples were also taken intermittently
at predetermined intervals during the 28-days dosing period and up to the last day
of the study, which was Day 42. Blood samples were taken from
v. cephalica antebrachii. Skin biopsies were taken from the area between the mid ventral to lateral abdominal
areas, using a 6 mm (diameter) skin biopsy device (Acu-Punch®, Acuderm® Inc., Fort
Lauderdale, FL 33309). Multiple plasma and biopsy samples were obtained from each
of 4 or 5 dogs. Subcutaneous fat deposits were carefully trimmed from the skin samples
and the skin samples were weighed. All plasma and skin samples were kept
[0048] The plasma samples and skin biopsy samples were analyzed using LC/MS/MS methodology.
All pharmacokinetic analyses were performed using Pharsight WinNonlin® Professional
v5.2.1 software.
Table 4: Pharmacokinetic (PK) Parameters on Day 28 of Dosing.
PK Parameter |
SNORK Plasma |
SNORK Skin |
RNORK Plasma |
RNORK Skin |
RS-NORK Plasma |
RS-NORK Skin |
AUC0-∞ |
1627 |
25710 |
1658 |
20376 |
3286 |
54187 |
t1/2 (hr) |
10.9 |
162.7 |
7.7 |
157.0 |
10.5 |
167.6 |
MRT (hr) |
11.3 |
159.0 |
14.1 |
159.1 |
12.8 |
169.3 |
AUC0-∞ = Area under the plasma concentration (or skin concentration) vs. time curves
t1/2 = Plasma or skin half-life MRT = Mean residence time
SNORK = S-norketotifen; RNORK = R-norketotifen; RS-NORK = total norketotifen |
[0049] Since norketotifen potently inhibits the release of histamine from pro-inflammatory
cells (Example 1) and acts as an inverse agonist at the histamine H-4 receptors (Example
3), and since norketotifen is accumulated in the skin (Table 4), those skilled in
the art will realize that the decreased availability of histamine together with the
inhibitory activity at the histamine H-4 receptor site will act synergistically to
reduce the G-protein-mediated signaling from dermal histamine H-4 receptors.
Example 5. Antipruritic activity
[0050] Antipruritic effects were tested
in vivo in CD-1 mice, females, 10 - 12 weeks, according to methods known in the art. The
hair was clipped over the rostral part of the back at the interscapular level of the
mice one day before the dosing. Before the testing, the mice were placed in individual
clear plastic cages for at least one hour for acclimation. After fasting for 1.5 hours,
the animals were dosed orally with the test article, dissolved in a vehicle consisting
of 1% methylcellulose/water, 10 mL/kg body weight. Sixty minutes after the oral dosing,
an intradermal injection of histamine (300 nmol in 20 µl phosphate buffered saline
(PBS), pH 7.4) was administered. Immediately after the histamine injection, the bouts
of scratches were counted for 40 min. Scratching induced by the histamine vehicle
PBS served as control.
[0051] Norketotifen was tested in escalating doses and in a supramaximal dose of 100 mg/kg.
JNJ7777120 and desloratadine were dosed orally with 20 mg/kg, which is within the
murine dose ranges used for those compounds in the art. The vehicle for the reference
compound JNJ7777120 was 20% hydroxypropyl-β-cyclodextrin in water. The vehicle for
the reference compound desloratadine was the same as the vehicle for norketotifen
(10 mL/kg of 1 % methylcellulose in water). The test results are shown in Figure 1.
The numbers of pruritic bouts are expressed in percent of Vehicle (100% corresponds
to 112 pruritic bouts). A test of the vehicle for JNJ7777120 demonstrated 112 bouts
of pruritus (not shown in Figure 1), which coincidentally was exactly the same number
of bouts obtained for the methylcellulose vehicle. The reference compound desloratadine
is a selective histamine H-1 inhibitor and the reference compound JNJ7777120 is a
selective histamine H-4 inhibitor.
[0052] Norketotifen was dose-dependently inhibiting histamine-induced pruritus and a supramaximal
dose (100 mg/kg) demonstrated complete inhibition. Scratches induced by the histamine-free
vehicle PBS (not shown in Figure 1) served as control (4 ± 2 bouts of scratching;
n = 6)
[0053] It was concluded that norketotifen potently and dose-dependently decreased histamine-induced
pruritus. The results from tests of a selective histamine-4 inhibitor and a selective
histamine-1 inhibitors demonstrate that histamine H-4 inhibition, but not histamine
H-1 inhibition blocks histamine - induced pruritus. The unexpectedly potent inhibition
of pruritus by norketotifen may in part be due to potentiation caused by simultaneous
expression of both histamine H-1 and histamine H-4 receptor inhibition by norketotifen.
Example 6. Exemplary oral dosage formulation
[0054] Formulations for oral administration of norketotifen (such as for example tablets,
capsules and syrups) have been developed.
Table 5. Tablet formulations
Ingredient |
Amount per tablet |
Amount per batch |
Norketotifen |
20 mg |
200 g |
Microcrystalline cellulose |
30 mg |
300 g |
Lactose |
70 mg |
700 g |
Calcium stearate |
2 mg |
20 g |
FD&C Blue #1 Lake |
0.03 mg |
300 mg |
[0055] The active ingredient is blended with the lactose and cellulose until a uniform blend
is formed. The blue lake is added and further blended. Finally, the calcium stearate
is blended in, and the resulting mixture is compressed into tablets using for example
a 9/32-inch (7 mm) shallow concave punch. Tablets of other strengths may be prepared
by altering the ratio of active ingredient to the excipients or to the final weight
of the tablet.
[0056] Those skilled in the art realize that oral formulations can be in the form of, for
example, a tablet, a capsule, a dog-treat, a cat-treat, a syrup or another form of
liquid formulation.
[0057] As used herein, the terms "pharmaceutically acceptable salts" or "a pharmaceutically
acceptable salt thereof' refer to norketotifen salts, which have been prepared from
pharmaceutically acceptable non-toxic acids. Exemplary pharmaceutically acceptable
acid addition salts for the compound of the present invention include acetic, benzenesulfonic
(besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,
hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic,
mucic, nitric, pamoic, pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric,
tartaric, and the like. The hydrochloride salt and the hydrogen fumarate salt are
particularly preferred.
[0058] The use of the terms "a" and "an" and "the" and similar referents (especially in
the context of the following claims) are to be construed to cover both the singular
and the plural, unless otherwise indicated herein or clearly contradicted by context.
The terms first, second etc. as used herein are not meant to denote any particular
ordering, but simply for convenience to denote a plurality of, for example, layers.
The terms "comprising", "having", "including", and "containing" are to be construed
as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise
noted. As used herein, the term mammal includes humans, dogs, and cats. Recitation
of ranges of values are merely intended to serve as a shorthand method of referring
individually to each separate value falling within the range, unless otherwise indicated
herein, and each separate value is incorporated into the specification as if it were
individually recited herein. The endpoints of all ranges are included within the range
and independently combinable. All methods described herein can be performed in a suitable
order unless otherwise indicated herein or otherwise clearly contradicted by context.
The use of any and all examples, or exemplary language (e.g., "such as"), is intended
merely to better illustrate the invention and does not pose a limitation on the scope
of the invention unless otherwise claimed. No language in the specification should
be construed as indicating any non-claimed element as essential to the practice of
the invention as used herein.
[0059] The invention will include all embodiments falling within the scope of the appended
claims.